Sequence-Based Design of /-Peptide Foldamers That Mimic BH3 Domains

摘要

The design of molecules that bind tightly and selectively to a specific site on a protein constitutes a fundamental challenge in molecular recognition. Finding high-affinity ligands for protein surfaces that bind to other proteins has proven to be particularly difficult.[1] Foldamers, oligomers with discrete folding propensities,[2] represent an unconventional source of ligands for protein-recognition surfaces,[3] but realizing this potential requires that we learn how to design sequences that contain unnatural building blocks and effectively mimic one of the surfaces involved in a given protein-protein interaction. Herein we show that systematic backbone modification throughout a natural protein-binding domain, a process we refer to as sequence-based design, can expeditiously generate foldamers that bind tightly and selectively to target protein surfaces.